Malaria is an infectious disease widespread in tropical and sub-tropical regions of Africa, Asia, and the Americas. In 2010 the World Health Organization estimated that there were over 219 million documented cases of malaria and between 660,000 and 1.2 million deaths from the disease (Nayyar, Lancet Infectious Diseases, 12:488-496, 2012). Malaria initially manifests with mild to severe symptoms including: chills, fever, fatigue, headache, and nausea. Later symptoms include severe anemia, and blood clotting, which can lead to brain damage and other complications, and death. Although five species of Plasmodium (P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi) can infect humans, the majority of malarial deaths are caused by P. falciparum and P. vivax. 
Plasmodium parasites are transmitted to a human host primarily through a bite from an infected mosquito. The parasites are released into the blood stream of the human host from the salivary glands of the infected mosquito and travel to the liver. At this stage, the parasites are called sporozoites. The sporozoites asexually reproduce in the liver, a process called tissue schizogony, to produce genetically identical copies of the sporozoites, called merozoites. The merozoites leave the liver and infect red blood cells, where they undergo several rounds of asexual reproduction (blood schizogony) to produce new merozoites for continued red blood cell infection. Some merozoites mature into sexual stage gametocytes that are infective to mosquitoes. When a mosquito bites an infected person, ingested gametocytes enter the mosquito gut where they mature. Mature male and female gametes fuse in the gut of the mosquito to form zygotes, which ultimately develop into sporozoites.
Current strategies for treating malaria include the use of antimalarial drugs such as chloroquine and artemisinin. These drugs work by targeting the parasite and therefore, it is possible for parasites to develop resistance to current therapeutics. Widespread drug resistance in Plasmodium spp. has undermined the effectiveness of many of antimalarials used commonly, particularly chloroquine (Hyde, Trends Parasitol, 21:494-498, 2005). Combination therapy is required to combat these resistant strains and preserve antimalarial effectiveness. Artemisinin-derived drugs such as artesunate and artemether are effective against multi-drug resistant strains of P. falciparum (Alin and Bjorkman, Am J Trop Med Hyg, 50:771-776, 1994; van Vugt et al., Trans R Soc Trop Med Hyg, 94:545-548, 2000), and are highly potent against asexual forms, rapidly reducing parasitemia (Price et al., Trans R Soc Trop Med Hyg, 91:574-577, 1997; and Angus et al., Antimicrob Agents Chemother, 46:778-782, 2002). However, effective monotherapy requires seven days of treatment, increasing the risk of resistance development through poor compliance. Indeed, artemisinin-resistant malaria has already emerged (Fairhurst et al., Am J Trop Med Hyg, 87:231-241, 2012). For this reason, artemisinin-derived drugs must be combined with at least one other antimalarial. For example, the WHO Tropical Disease Research program, the Medicines for Malaria Venture (MMV), and GlaxoSmithKline formed a partnership to build upon a two-drug antimalarial including chlorproguanil and dapsone (Winstanley, Trop Med Int Health, 6:952-954, 2001) by adding artesunate to the combination.
The three-drug therapy including chlorproguanil, dapsone and artesunate is called CDA. Unfortunately, this therapy has negative side effects for some individuals who become infected with malaria parasites. The combination of chlorproguanil and dapsone can produce hemolysis, shorten red blood cell lifespan and induce methemoglobinemia, particularly in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals to the point that this combination was banned for malaria-infected individuals with this disorder. Due to this side effect, GlaxoSmithKline removed CDA from the market in 2008 (Luzzatto, Lancet, 376:739-741, 2010). The same side effects were observed during the use of CDA for treating uncomplicated malaria in G6PD-deficient children (Van Malderen et al., Malaria J, 11:139, 2012).
Therefore, there remains a need for an antimalarial therapy regimen that is essentially resistant to evasion by Plasmodium spp. In addition, there remains a need for antimalarials that are safe for use by G6PD-deficient individuals.